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89 Cards in this Set
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example of autoimmune disease involving multiple proteins but only one cell type
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Hashimoto's thyroiditis
e.g where antibodies to microsomal proteins and thyroglobulin can both occur in the same patient (both proteins on thyroid follicular cell) |
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Goodpasture's disease
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autoimmune disease where circulating antibodies against type IV collagen are found. Type IV collagen is found primarily in the basement membranes of blood vessels, such blood vessels being abundant in the kidney and lungs
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examples of organ-specific autoimmune diseases
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Autoimmune hemolytic anemia
Myasthenia gravis Hashimoto’s thyroiditis Goodpasture’s syndrome Grave’s disease Immune thrombocytopenic purpura Pernicious anemia Chronic active hepatitis Juvenile-onset diabetes mellitus Primary biliary cirrhosis Multiple sclerosis Pemphigus Addison’s disease |
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General categories of anemia
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erythrocyte underproduction or increased erythrocyte destruction
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what causes underproduction of rbc's?
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failure of the bone marrow, such as in aplastic anemia, nutritional deficiencies (e.g., iron deficiency), in response to toxins (e.g., lead poisoning), or malignancies that crowd out normal erythropoietic elements in the bone marrow
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what will the blood smear show with underproduction of rbc's?
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paucity of early RBCs (reticulocytes)
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What are some causes of increased erythrocyte destruction?
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hemoglobinopathies (e.g., sickle cell anemia), enzyme deficiencies (e.g., G6PD deficiency) or red cell membrane abnormalities (e.g., hereditary spherocytosis), and immune-mediated RBC destruction
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What does the smear show with increased rbc production due to anemia?
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the bone marrow usually attempts to compensate for the anemia by increasing production and releasing erythrocytes a little earlier than normal. This results in increased numbers of early RBCs (reticulocytes) in the peripheral blood.
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On a typical Wright-Giemsa stain of peripheral blood what do reticulocytes look like?
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reticulocytes appear to have a slight purple tint. This gives rise to the term “polychromasia”, meaning that the erythrocytes have slight varying shades of color. Reticulocytes are erythrocytes that still contain detectable amounts of RNA.
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What is the best stain for detecting reticulocytes?
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New Methylene Blue stain. This stain causes RNA to appear purple.
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What is the underlying pathology of AIHA?
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production of Ab's to RBC surface proteins
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How is AIHA divided into three categories (on what characteristics) and how does this predict symptoms?
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depending upon the thermal characteristics of the pathogenic antibodies. In part, the thermal characteristics of the auto-antibodies directly affect the resulting symptoms. It is not known why some antibodies react only in the cold and why these particular antibodies appear after infections with Mycoplasma pneumoniae or infectious mononucleosis.
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What type of auto-antibodies are seen in WAIHA?
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mostly IgG
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What are characteristics of WAIHA?
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Approximately 80% of the autoimmune hemolytic anemias are of the warm type. For the most part, red blood cell destruction occurs by retention of the IgG-coated erythrocytes in the spleen (opsonization by macrophages) rather than intravascular hemolysis (complement-mediated lysis). For this reason, splenomegaly (and to a lesser extent, hepatomegaly)
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Signs/symptoms of WAIHA
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clinical presentation variable; may be subclinical, acute or severe. Symptoms include fatigue, dyspnea, pallor, and with a severe anemia signs of cardiac insufficiency. can also include elevated heart rate and depressed ST segment on ECG
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why is heart muscle so susceptible during severe anemia?
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Not only will it be deprived of oxygen (because of the poorer oxygen-carrying capability of blood) but it will also be called upon to work harder (increased heart rate), further increasing its need for oxygen.
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What's the direct antiglobulin test (DAT)?
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Coomb's test:
several ways but each involve demonstrating autoAb on RBC surface. RBCs washed w/ saline to remove unbound plasma, then mixing, and centrifugation. Afterwards, saline decanted and RBC pellet resuspended. can then be used for testing purposes. WAIHA--Ab's remain bound despite the wash steps. These Ab's are detected in the DAT test. |
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Will a pt with WAIHA have a positive or neg Coomb's test (DAT)?
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Positive: in WAIHA, antibodies remain bound to the RBCs, despite the wash steps. These antibodies are detected in the DAT test. Rarely, a patient with all the signs and symptoms of WAIHA will have a negative DAT test. often, the problem can be traced to the particular test method used in the DAT test. With modifications to the DAT test, anti-RBC antibody can be shown to be present
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What causes WAIHA?
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~50% of pts w/ WAIHA, no specific etiology (idiopathic)
In the other half w/ an underlying cause: most commonly a drug to which autoantibody production can be traced. |
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in idiopathic WAIHA what are the Ab's to?
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antibodies to the Rh blood group family can be detected, often in high titer
Other blood group antigens can also be found |
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What is the Rh blood group?
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a highly complex family of more than 45 different blood group antigen specificities.
The Rh antigens appear to be red cell specific, appearing early during development of red blood cells, and have not been found on other body tissues On a molecular level, Rh is actually a family of proteins. Rh Associated Glycoprotein (RhAG) is always found in association with either RhD or RhCE proteins |
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What are the basic Rh specificities?
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D, C/c, and E/e:
capital and lower case refers to two different alleles at same locus No d antigen, (but sometimes used to denote the absence of D) D is either present or absent. For the other two, a person can have either the C or c as well as the E or e blood group antigen |
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What is erythroblastosis fetalis and how is the Rh Ag involved?
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another immune-mediated mechanism of hemolysis.
not autoimmune in nature. It occurs when an Rh D- mother carries a child from an Rh D+ father. The baby is Rh D+, since the paternal allele will result in expression of the Rh D protein. During birth, the Rh D+ red blood cells from the baby can cross the placenta in sufficient numbers to immunologically sensitize the mother to the Rh D antigen. During a second pregnancy, those anti-Rh D antibodies can cross the placenta and cause a severe hemolytic anemia in the unborn fetus. |
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What is RhAG?
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Rh Associated Glycoprotein always found in association with either RhD or RhCE proteins
on the red blood cell membranes as tetramers The RHD protein produces the D antigen, or most of its components. The RhCE protein produces the Cc and Ee antigens or their variants |
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What about drug-induced WAIHA?
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WAIHA accounts for about 12-20% of AIHAs. Certain drugs, most notably penicillin and cephalosporins, can associate with the red blood cell membrane and induce an immunologic response. PCN is too small to induce immune response alone but it is attached (as a "hapten") to a carrier protein--both then elicit Ab's.
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Tx for drug-induced hemolytic anemia?
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discontinue the offending drug and provide supportive therapy. It usually subsides spontaneously, as the drug clears the circulation.
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What happens to pts on long-term alpha-methyldopa?
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10-20% pts develop a positive Direct Antiglobulin Test (DAT) and 0.5-1% develop hemolytic anemia. The mechanism for autoantibody development is unknown, but may involve a direct effect on T lymphs or changes in a RBC Ag. Lab shows changes similar to WAIHA. anti-RBC antibodies don't bind to alpha-methyldopa, bind directly to RBC antigens, as in idiopathic WAIHA. The DAT positivity is dose dependent and dissipates slowly after drug discontinued. DAT can still be positive after 2 years.
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What's the association b/w AIHA and CLL?
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estimated 1000 new AIHA pts secondary to CLL each year
AIHA=most common disease assoc. w/ CLL. likely that the Ab's to Rh family or Rh complex (includes additional proteins besides RhAG, RhD, and RhCE) exact etiology unknown-speculated that CLL induces immune dysregulation. AutoAb not derived from malignant B clone--polyclonal from non-malignant B lymphocytes. |
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Lab findings in WAIHA?
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polychromasia, reticulocytosis, nucleated rbc's, spherocytosis
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What's polychromasia?
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slight variation in color of RBCs (blood smear w/ wright-Giemsa) due to RNA still present from retics
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What's reticulocytosis?
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increased no. retics in circulation. id'd by new methylene blue staining for RNA
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What are nucleated rbc's?
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early rbc's in circulation (earlier than retics) which still contain nucleus. found in assoc w/ dramatic increase in RBC production (anemia)
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What's spherocytosis?
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nl rbc's=discoid and can deform to pass through splenic sinuses. in WAIHA, rbc's often caught by splenic mac's which eats a piece of it. the rbc reseals and reciruculates w/ less membrane resulting in spheroid shape. central pallor gone on blood smear.
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Treatment options for WAIHA?
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1. none- most pts mildly anemic
2. steroids - for ~80% pts w/ IgG induced hemolytic anemia 3. iv IgG - block opsonization by splenic macs 4. splenectomy - espec. for IgG type (e.g. WAIHA) 5. transfusion - in emergency 6. Cytotoxic agents 7. Cyclosporine A 8. Plasmapheresis |
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4 phases of steroid (prednisone) tx?
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1. initial high dose
2. tapered decrease to assess permanency of results 3. stabilize at low maint dose or increase D w/ relapse 4. assess if other tx necessary? |
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What's the mechanism of i.v. IgG in treating AIHA?
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competitive inhibition for uptake by Fc receptors on splenic mac's so they're less able to opsonize IgG coated rbc's. less effective than steriods but more eff w/ severe dz.
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When would you give a transfusion to treat AIHA?
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life threatening situation for anemia until other tx begins to work. often the transfused blood will be destroyed which can be nephrotoxic.
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Should cytotoxic agents be used to treat AIHA?
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(e.g cyclophosphamide) alkylating agents toxic to many hematopoietic cells and can have severe side effects like neutropenia leading to sepsis. NOT 1st choice tx.
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How is cyclosporine used to treat AIHA?
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potent immunosuppressive agent inhibits IL-2 synth and impairs the fxn of T lymphs. Little evidence other than a trial of 7 pts who report signif imprvment.
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What is plasmapheresis?
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autoAb is in the pt's plasma and can be removed by exchanging it for nl plasma--only temporary sol'n. rarely used b/c autoAb widely distrib in xtravascular space.
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What is cold AIHA?
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~20% of AIHA:
transient and chronic forms usually caused by IgM to blood group Ag's (usually not Rh-unlike WAIHA) |
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When does the transient form of CAIHA occur?
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younger pts as rare complication of infectious dz (typically during recovery)
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When does the CHRONIC form of CAIHA occur?
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older adults, often assoc w/ B lymph neoplasms.
usually less severe than WAIHA |
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Why is it called "cold" AIHA?
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b/c Ab's have the unusual characteristic of binding rbc's at cooler temps and poorly at 37 degrees C - Ab's dont bind in warm body core but fingers, toes, nose, ears.
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what's the pathology of CAIHA?
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IgM Ab's bind RBCs in periphery (cooler) and complement is activated to C3b (it stops there b/c of cool temp). when RBCs recirc to body core, IgM sloughs off but C3b still bound and cell can be opsonized or C3b degraded.
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What is CAIHA most associated with?
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the recovery phase of illness, especialy infection by mycoplasma pneumo (most cases develop cold agglutinins to a titer of at least 1:32; but only a small number develop anemia as a consequence)
also caused by CMV (anti-I) EBV (anti-I), rubella (anti-Pr)and varicella (very rare) |
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How is transient CIAHA treated?
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unless severe anemia, no tx--spontaneous resolution
supportive tx only (e.g. warmth) |
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How severe is chronic CAIHA?
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usually mild to moderate, stable anemia
IgM usually monoclonal (unlike transient CAIHA) |
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what is chronic CAIHA associated with?
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lymphoproliferative dz in the elderly (lymphoma, CLL, myeloma, waldenstrom's macroglobulinemia)
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what's the treatment of chronic CAIHA?
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treat the underlying cause (lymphoproliferative dz)--often this is impossible due to cancer resistance to tx
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why do cold agglutinins give rise to "spurious" lab results?
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b/c most hematology tests performed at room temp. automated analyzers see clumps of RBC's as abnl. (shows spurious macrocytosis and decreased RBC count--b/c they're stuck together; MCV and MCHC also off)
solution=warm it to 37 and repeat the test. can also cause blood typing errors |
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besides anemia, what else can go wrong with cold agglutinins?
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clumping of RBCs--venous obstruction resulting in cyanosis and Raynaud's (spasm of digital arteries). causes skin blanching and pain due to cessation of BF
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what are struma lymphomatosa, lymphadenoid goiter, and chronic lyphocytic thyroiditis?
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Hashimoto's autoimmune thyroiditis
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what characterizes Hashimoto's?
What does it cause? |
imflammation of thyroid gland
decreased fxn of the thyroid gland |
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where is monoiodotyrosine made?
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in the colloid of a thyroid follicle
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How is T4 formed? T3?
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2 DIT residues are coupled in the colloid
one MIT residue couples to a DIT |
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How does Hashimoto's present clinically?
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painless enlargement of the thyroid
PE: nontender goiter, smooth or nodular, firm, and more rubbery than nl thyroid *hypothyroidism common |
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What causes enlargement of the thyroid gland in hashimoto's and what are the consequences?
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inflammatory cells destroy those of the thyroid causing scarring.
Damaged thyroid cells can't produce TH resulting in hypothyroidism |
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If a pt presents with fatigue, difficulty concentrating, and weight gain, what's the likely Dx?
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HYPOthyroidism
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What are add'l symptoms of hypothyroidism seen in old ppl besides fatigue, difficulty concentrating and weight gain?
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hoarseness, confusion, depression, hair loss
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How can Hashimoto's cause HYPERthyroidism?
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causes overactive thyroid resulting in increased TH release as cells are destroyed.
usually short followed by a period of normal thyroid fxn. eventually, scarring leads to HYPOthyroidism |
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Who gets Hashimoto's?
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any age but mostly middle aged women.
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What's the epidemiology of autoimmune thyroiditis?
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takes months to years to develop
1:10,000 ppl in US (F:M=8:1) most common in women and w/ family history increased incidence in chromosomal disorders (Turner's, Downs, Klinefelter) |
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What's the most common cause of primary hypothyroidism in N. America?
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autoimmune thyroiditis
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what does histology show on exam of autoimmune thyroiditis?
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extensive lymph infiltrates in the thyroid w/ Lymphoid FOLLICLES
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What are symptoms of Hashimoto's?
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same as hypothyroidism:
cold intolerance weight gain fatigue constipation neck mass/goiter or atrophic/smalller thyroid late in dz |
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what other diseases is Hashimoto's assoc. w/?
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endocrine disorders caused by the immune system.
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What's PGA II
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Combo of:
Hashimoto's thyroiditis Adrenal Insufficiency Type 1 Diabetes Type 2 polyglandular autoimmune syndrome |
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What's PGA I?
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Hashimoto's plus
HYPOparathyroidism adrenal insufficiency, fungal infections of mouth/nails together called Type 1 polyglandular autoimmune syndrome |
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What's the hallmark of dx for Hashimoto's?
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circulatin auto-Ab's to thyroglobulin and thyroid microsomal Ag (primarily enzyme thyroid peroxidase)
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How are Ab's to autoimmune thyroiditis measured?
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now by agglutination assays or ELISA
present in serum of >90% pts with hashimoto's thyroid peroxidase Ab's more common than anti-thyroglobulin |
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what happens if Hashimoto's pts don't present w/ serum Ab's?
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autoAb production may be localized to intrathyroidal lymphs and plasma cells
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How is thyroid fxn evaluated
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measure TSH and T4 levels
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why is measurement of plasma thyroxine levels possibly confounding?
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b/c only ~0.3% of t4 is free in plasma. the rest is bound to TBG, prealbumin, and albumin
free amount not very clinically useful. better to use free thyroxine index (ratio T4: TBG) TSH most sensitive indicator of thyroid hormone status |
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How is T4 found in plasma?
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70% T4 bound to thyroxine binding globulin
20% to thyroxine binding prealbumin 10% to albumin 0.3% free in plasma |
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what's the free thyroxine index?
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FTI: ratio of T4 ot thyroxine binding globulin.
not a very good measure b/c amt of T4 estimated and inaccurate |
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what does elevated TSH indicate?
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hypothyroidism
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what does elevated TSH w/ nl T4 indicate?
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subclinical hypothyroidism
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What does elevated TSH w/ reduced T4 indicate?
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true hypothyroidism
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what do thyroid cells look like with thyroid enlargement?
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slightly larger than normal
acidophilic(pink) called Hurthle cells packed w/ mitochondria |
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what does the histology of the thyroid gland look like w/ enlargement?
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epithelial destruction, lymph cell infiltrates, fibrosis
Hurthle cells follicular spaces shrink colloid absent/sparse clusters of mac-like cells follicles/germinal centers prominent plasma cells equal no. T and B lymphs |
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would you see foreign body giant cells or granulomas in hashimoto's?
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No, only in subacute thyroiditis
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can anything else besides autoimmune thyroiditis cause an enlarged thyroid? WHat?
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Yes many things including benign goiter, cancer, other types of thyroiditis
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what's the link b/w hashimoto's and genetics?
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~50% first degree relatives of affected pts have circulating thyroid Ag's
assoc. w/ HLA Ag's: DR4 and DR5 (inconsistent b/w ethnic grps) |
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do Ab's cause dz in Hashimotos?
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TPO Ab's are complement fixing and may be cytotoxic but evidence is limited (nl transplacental Ab passage of anti-TPO don't cause thyroid damage)
speculated role of cytotoxic T cells |
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what happens when mice are injected w/ thyroid reactive T lymphs?
what might this mean? |
induce thyroiditis
tells us the dz in humans may be T cell mediated |
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in hashimotos, how does lymph infiltrate cause destruction of thyroid follicular cells?
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in hashimotos, thyrocytes express both Fas and FasL
IL-1 beta causes their apoptosis fas-fas ligand interxn may be involved |
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treatment of hashimoto's thyroiditis?
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lifelong thryoid hormone replacement (L-thyroxine) to decrease goiter size and treat hypothyroidism
titration based on TSH levels |
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does hashimotos ever resolve?
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hypothyroidism can be transient on occasion
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